Wang Qi, Huang Taida, Zheng Zihan, Su Yixun, Wu Zhonghao, Zeng Cong, Yu Guangdan, Liu Yang, Wang Xiaorui, Li Hui, Chen Xiaoying, Jiang Zhuoxu, Zhang Jinyu, Zhuang Yuan, Tian Yi, Yang Qingwu, Verkhratsky Alexei, Wan Ying, Yi Chenju, Niu Jianqin
Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
Department of Histology and Embryology, Third Military Medical University, Chongqing 400038, China.
Sci Transl Med. 2025 Apr 2;17(792):eadn9980. doi: 10.1126/scitranslmed.adn9980.
Reproducing the pathophysiology of human multiple sclerosis (MS) in animal models is critical to identifying mechanisms triggering demyelination and to developing early intervention strategies. Here, we aimed to model overactivated Wnt (wingless-related integration site) signaling previously shown in postmortem brain tissues of patients with MS by inducing experimental autoimmune encephalomyelitis (EAE) in and mice. These mice have overactivated Wnt signaling in oligodendrocyte precursor cells (OPCs) because of a conditional knockout of the pathway repressor adenomatous polyposis coli (APC). EAE mice exhibited increased expression of markers for Wnt activation such as Axis inhibition protein 2 (AXIN2) and Wnt inhibitory factor 1 (WIF1) in OPCs and showed exacerbated EAE progression in both the spinal cord and the brain. Genetic or antibody-mediated ablation of CC-chemokine ligand 4 (CCL4) prevented infiltration of CD4 T cells and arrested disease progression in these mice. A characterization of CNS (central nervous system) immune cell clusters identified an augmented subpopulation of NK1.1CD11bGr-1 cytotoxic macrophages in EAE mice. Microinjection of this subpopulation of macrophages into the brains of wild-type C57/B6J mice was sufficient to induce demyelination. Ablation of CD4 T cells prevented the effects of Wnt overactivation on demyelination and immune cell infiltration. Antagonizing chemokine receptor 5 (CCR5) using a European Medicines Agency-approved drug, maraviroc, reduced immune cell infiltration, alleviated demyelination, and attenuated EAE progression. We found an OPC-orchestrated immune cellular network that instigates early demyelination, provides insight into MS pathophysiology, and suggests avenues for early interventions.
在动物模型中重现人类多发性硬化症（MS）的病理生理学对于确定引发脱髓鞘的机制以及制定早期干预策略至关重要。在此，我们旨在通过在 和 小鼠中诱导实验性自身免疫性脑脊髓炎（EAE），对先前在MS患者尸检脑组织中显示的过度激活的Wnt（无翅相关整合位点）信号进行建模。由于通路抑制因子腺瘤性息肉病 coli（APC）的条件性敲除，这些小鼠的少突胶质前体细胞（OPC）中Wnt信号过度激活。EAE小鼠的OPC中Wnt激活标志物如轴抑制蛋白2（AXIN2）和Wnt抑制因子1（WIF1）的表达增加，并且在脊髓和大脑中均显示出EAE进展加剧。CC趋化因子配体4（CCL4）的基因或抗体介导的消融可防止CD4 T细胞浸润并阻止这些小鼠的疾病进展。对中枢神经系统（CNS）免疫细胞簇的表征确定了EAE小鼠中NK1.1CD11bGr-1细胞毒性巨噬细胞的亚群增加。将该巨噬细胞亚群显微注射到野生型C57/B6J小鼠的大脑中足以诱导脱髓鞘。CD4 T细胞的消融可防止Wnt过度激活对脱髓鞘和免疫细胞浸润的影响。使用欧洲药品管理局批准的药物马拉维罗拮抗趋化因子受体5（CCR5）可减少免疫细胞浸润、减轻脱髓鞘并减弱EAE进展。我们发现了一个由OPC精心策划的免疫细胞网络，该网络引发早期脱髓鞘，为MS病理生理学提供了见解，并提出了早期干预的途径。
